Category Archives: Heart

It bears emphasis that the results of the present study are entirely analogous to those that were reported recently with amiodarone, which was shown to suppress TNF-а production in endotoxin-stimulated mononuclear cells, but which had no measurable effect on peripheral circulating levels of TNF-а in a subset of patients with nonischemic cardiomyopathy enrolled in the Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure.
A second interesting and potentially important finding in this study is that there was a significant dose-dependent increase in IL-6 levels in the vesnarinone-treated patients who died, when compared to the nonsurvivors who received placebo (Fig 4, right, B). Although the mechanism for the increase in IL-6 levels in the nonsurvivors who were treated with vesnarinone is not known, it is interesting to note that previous reports have shown that the treatment of patients with agents that elevate cyclic adenosine monophosphate levels, such as dobut-amine and pentoxifylline, has resulted in increased circulating levels of IL-6.”

The results of this clinical study, in which we examined the anticytokine properties of vesnarinone in patients with moderate-to-advanced heart failure, suggest that neither the 30-mg/d dosage nor 60 mg/d dosage of vesnarinone had any measurable effect on the peripheral circulating levels of cytokines and cytokine receptors. The finding that vesnarinone had no discernible effect on circulating levels of TNF-а and IL-6 in humans in vivo differs from experimental data which showed that vesnarinone inhibited the production of proinflammatory cytokines. Indeed, several in vitro studies have shown that vesnarinone suppresses the production of TNF-а and IL-6 in various human cell lines, including peripheral lymphocytes, monocytes, T-cell lines, and microglial cells. Moreover, an in vivo study of endotoxemia in rabbits showed that IV vesnarinone reduced the circulating levels of TNF-а. Although the reasons for the discrepancy between the previous in vitro/in vivo findings are not clear, there are several possible explanations. buy flovent inhaler

Since pentoxifylline, another phosphodiesterase inhibitor, was effective in reducing levels of TNF-a in patients with idiopathic dilated cardiomyopathy in a previous study, we also examined vesnarinone-induced changes in cytokine levels in relation to the etiology of heart failure. Figure 3 shows the fold change in TNF-a and IL-6 levels from baseline to 24 weeks (ie, 24 weeks/baseline levels), in relation to the etiology of heart failure in the three treatment groups. As shown in the Figure 3, the fold change in TNF-a and IL-6 did not differ significantly between patients with ischemic and nonischemic etiology of heart failure in the three treatment groups. buy antibiotics online

Table 1 shows the demographic characteristics of the study population. The mean age of the patient cohort was 62 years, of which most (77%) were men. Approximately 90% were in NYHA class III functional status at the time of enrollment, and 60% of the patients were categorized as having an ischemic cardiomyopathy. As shown, there were no significant differences in age, sex, etiology of heart failure, ejection fraction, serum sodium level, and weight among patients in the placebo, 30-mg vesnarinone, and 60-mg vesnarinone groups. There was, however, a higher proportion of NYHA class IV patients in the vesnarinone groups (p = 0.02). These characteristics are similar to those previously reported for the entire cohort of VEST patients.
Table 2 shows the baseline values for the circulating cytokines and cytokine receptors for patients who received placebo, 30 mg of vesnarinone, and 60 mg of vesnarinone. As shown, there were no significant differences in baseline levels of cytokines or cytokine receptors among the three treatment groups. Figure 1 shows the changes in TNF-a and TNF receptors at 24 weeks compared to baseline values. Figure 1, top, A shows that there was a small increase in the circulating levels of TNF-a in each of the three treatment groups at 24 weeks, which was statistically significant in only the 30-mg vesnarinone group (p = 0.04). However, there was no significant difference in the levels of TNF-a as a function of time among patients who received placebo, 30 mg of vesnarinone, or 60 mg of vesnarinone (p = 0.77). itat on

Neither the cytokine nor the cytokine-receptor data were normally distributed; therefore, the data were subjected to logarithmic transformation prior to all statistical analyses. However, in order to permit comparison with results from other studies, both the cytokine and cytokine-receptor data are presented as mean ± SEM on the untransformed scale. Analysis of variance (ANOVA) was used to compare continuous variables in the placebo, 30-mg vesnarinone, and 60-mg vesnarinone groups at baseline. The x2 test was used for comparison of categoric variables. Cytokine levels at baseline and at 24 weeks were compared between the treatment groups using a repeated-measures factorial ANOVA. The fold change in cytokine and cytokine-receptor levels (ie, ratio of levels at 24 weeks to levels at baseline) as a function of survival was compared between the treatment groups using a factorial ANOVA. canadian neighbor pharmacy

Circulating Levels of Cytokines and Cytokine Receptors
Plasma tumor necrosis factor (TNF)-a, interleukin (IL)-6, soluble TNF-receptor type 1 (sTNFR1), soluble TNF-receptor type 2 (sTNFR2), and soluble IL-6 receptor (sIL-6R) levels were obtained at baseline and at 24 weeks of follow-up for each patient. If the patient had a recent infection, the cytokine and cytokine receptors were drawn 2 weeks after the resolution of the most recent infection. All patients were receiving stable doses of angiotensin-converting enzyme inhibitors, diuretics, digoxin, and/or vasodilators for 30 days prior to obtaining baseline measurements. Circulating levels of cytokines and cytokine receptors were measured using an enzyme-linked immunosorbent assay (ELISA; R&D Systems; Minneapolis, MN) that measures “total” TNF and IL-6 (ie, free [unbound] cytokine and cytokine bound to receptors). There are several aspects of the methodology used in the analysis of this large clinical database that bear further emphasis.

Previous studies, suggest that proinflammatory cytokines may contribute to disease progression in heart failure by virtue of the direct toxic effects that these molecules exert on the heart and the circulation. Accordingly, there has been increasing interest in developing therapeutic agents with anticytokine properties that might be used as adjunctive therapy for patients with moderate-to-advanced heart failure. Vesnarinone is a positive inotropic agent that enhances cardiac contractility through multiple mechanisms, including an increase in the inward calcium current attributable to the phosphodiesterase inhibitory properties of this compound. Previous small-scale clinical studies with vesnarinone have shown salutary effects on the quality of life, as well as morbidity and mortality in patients with advanced heart failure. canadianfamilypharmacy